Avoiding Resistance Triggers: New Antimicrobial Strategies

Antibiotics and antifungals have dramatically reduced deaths from microbial infections since World War I, but their value is increasingly being eroded by increasing drug resistance. However, new strategies are being developed that aim to target infection, while avoiding the pathways that typically trigger antimicrobial drug resistance.

One of these strategies comes from researchers at the Keck School of Medicine at the University of Southern California. They have developed a new type of drug based on an existing natural molecule known as theta-defensin, as described in a recent Scientific reports paper. Old world monkeys produce these cyclic peptides naturally, but great apes such as gorillas, bonobos, chimpanzees, and humans do not.

“The old world monkeys that make these natural molecules in extraordinarily high amounts every day are incredibly resistant to experimental sepsis. They are around 10,000 times more resistant to endotoxins [which contributes to sepsis] than humans, ”said Michael Selsted, professor of pathology at Keck and co-lead author of the study. OMIC clinics.

Selsted is also the co-founder and CSO of Oryn Therapeutics, a biotechnology company created to develop these molecules and bring them to the clinic. He said the discovery of old world monkeys was what set the company on this path 20 years ago.

The recent study tested a theta-defensin designed to target infections even better than natural molecules found in monkeys.

“Traditional antibiotics, which are currently used clinically, interact directly with bacteria which they directly kill or inhibit their growth. But the problem is, bacteria have an immense capacity to adapt and evolve quickly, ”explained Justin Schaal, assistant professor and colleague of Selsted in Keck, as well as the first author of the recent study.

Theta-defensins take a different approach, interacting directly with the host and only indirectly with the microbe, they clear infections by stimulating the host’s immune system to attack the pathogens that cause them.

Schaal’s modified theta-defensin has shown good results in a preclinical animal study against Klebsiella infections. It’s specially designed to target hard-to-treat gram-negative bacteria, but other researchers and companies are working in this area. For example, Atox Bio biotechnology is working on the development of similar immune modulators, but instead focuses on serious Gram-positive bacterial infections.

One advantage of theta-defensins is that they are small and stable and do not trigger a strong immune response. “This class of molecules is not expected to generate an anti-drug antibody response that would neutralize it and render it useless,” said Selsted.

They could also be used to target a range of pathogens, which is not possible with standard antibiotics. Oryn’s research team is already working on the development of antifungal drugs based on this approach.

“What we just published demonstrates that the traditional approach to antibiotic development is not the only solution,” Schaal said.

Cesar de la Fuente, assistant professor at the University of Pennsylvania, agreed. He also takes a different approach with his colleagues and instead uses artificial intelligence (AI) to research new antimicrobials, which he says are badly needed.

“Antibiotic-resistant infections are expected to kill 10 million people per year by 2050, which translates to 1 death every 3 seconds… It is important to stress that these drugs are not only useful in curing deadly infections, but are also crucial for modern medicine, “he said.” Interventions such as organ transplants, chemotherapy treatments, childbirth and surgeries would not be feasible without effective antibiotics. “

de la Fuente and his colleagues recently published an article on this subject in the journal Nature Biomedical Engineering. They used the human body as a source of potential new antimicrobials by developing an algorithm to automatically search among thousands of potential drug candidates.

They found several peptides that exhibited antibacterial activity and appeared to attack the bacteria’s outer membrane, a process that appeared to trigger less drug resistance than more conventional antibiotics.

Besides being able to sift through large amounts of data, AI has the advantage of speeding up the process. “AI can help speed up the time it takes to discover new antimicrobials and reduce the costs associated with this process. It currently takes over 10 years and costs over $ 1 billion to develop a new drug; for context, that’s more than the budget NASA has to take a rocket to the moon.

This could help solve a persistent problem in antibiotic development, namely that high development costs discourage many pharmaceutical and biotech companies from developing these drugs due to the low return on investment.

Selsted also wants to make more use of AI at Oryn to help design better drug candidates. “Now that we have enough experience, we can start applying AI algorithms to generate molecules whose characteristics are arguably even more powerful,” he said.

“One of the things AI is really good at is developing three-dimensional models… you need to have a high-resolution starting three-dimensional structure of at least one of the compounds you’re dealing with. There are no crystal structures of these cyclic molecules that we are working with. But we have crystallized several of them. So we’re on the verge of being able to take very high-resolution three-dimensional images and start this AI investigation. “

About Hector Hedgepeth

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